Inositol is a cyclohexane modified at each carbon center by a hydroxyl group:
The compound therefore exists in nine possible stereoisomeric forms:
Of the possible stereoisomers, myo-inositol is the form that occurs most widely in nature. It is a structural component of biologically important compounds that function to generate second messengers in eukaryotes, such as, for example, phosphatidylinositol (PI) and phosphorylated derivatives of PI.
scyllo-Inositol (also known as scyllitol) is also known to occur in nature. In its most stable conformation, scyllitol may be represented as a chair with hydroxyl groups in the six equatorial positions:

The use of inositol stereoisomers in methods of preventing, treating, and diagnosing disorders of protein folding or aggregation have been reported. See, e.g., PCT International Publication No. WO2004/075882; McLaurin et al. (2000) J. Biol. Chem. 275:18495. These methods may therefore prove useful in the prevention, treatment, and diagnosis of amyloidoses such as, for example, Alzheimer's disease. Scyllitol has been used in human clinical trials for the treatment of Alzheimer's disease. See also PCT International Publication Nos. WO2007/041855 and WO2007/119108. The availability of chemically pure stereoisomers of inositol in significant chemical quantities is therefore of critical importance in the development of effective therapeutics in these areas.
The synthesis of scyllitol by chemical, enzymatic, and microbial methods has been reported. For example, Anderson et al. (1948) J. American Chem. Soc. 70:2931 describe the formation of inositol stereoisomers, including scyllitol, by the Raney nickel-catalyzed hydrogenation of hexahydroxybenzene.
Kiely et al. (1968) J. American Chem. Soc. 90:3289 describe a multi-step chemical synthesis of scyllitol starting from 3-O-benzyl-1,2-O-isopropylidene-6-β-triphenylmethyl-α-D-glucofuranose.
DE3405663 describes a process for the preparation of scyllo-inositol from myo-inositol via myo-inosose, in which the mixture obtained after the oxidation is subjected to an esterification reaction in which a well-crystallizing ester of myo-inosose is formed. The ester is then converted into scyllo-inositol by reduction and hydrolysis.
The process for conversion of myo-inositol to scyllo-inositol can be an enzymatic process, for example a bio-conversion process. European Patent Application Publication No. EP 1 674 578 A1, describes an NAD+-independent enzyme for converting myo-inositol into scyllo-inosose and another enzyme that stereospecially reduces scyllo-inosose into scyllitol. This reference also describes a microorganism that reportedly converts myo-inositol into scyllo-inositol. The disclosure of EP 1 674 578 A1 is incorporated herein by reference as it relates to this process. PCT publication number WO 2011/100670 describes a similar bio-conversion of myo-inositol into scyllo-inosose and scyllo-inositol, the disclosure of which is incorporated herein by reference as it relates to this process.
Husson et al. (1998) J. American Chem. Soc. 307:163-165 describes the equilibration of diasteroisomers of sugars by Raney nickel, wherein myo-inositol in water is refluxed with Raney nickel to form a mixture of inositols containing 20-30% of scyllo-inositol.
Reagents useful in the complexation and purification of scyllitol have also been reported. For example, Weissbach (1958) J. Org. Chem. 23:329 describes the formation of scyllitol diborate during the course of reduction of scyllo-myo-inosose with sodium borohydride.
Scyllitol diborate precipitates from the solution as a white solid and could be washed with small amounts of water. According to Weissbach, the compound could also be generated by heating scyllitol in an aqueous borate solution at 100° C.
Vogl et al. (1969) J. Org. Chem. 34:204 also reported the synthesis and characterization of scyllitol diborate. In their method, myo-inositol was biologically oxidized to myo-inosose-2, which was then reduced using sodium borohydride to yield a mixture of borate complexes of scyllitol and myo-inositol. These complexes could be separated due to differences in their solubility. Scyllitol diborate was then converted to scyllitol by treatment with sulfuric acid and methanol. According to Vogl et al., attempts to isomerize myo-inositol directly to scyllitol were unsuccessful.
The above-described methods to synthesize scyllitol either involve inefficient multi-step chemical routes that typically rely on the use of toxic organic solvents or require enzymatic or microbial steps that make large scale production of scyllitol challenging. There is thus a need for improved methods of synthesis of scyllitol and its derivatives.